ANGPTL3 deficiency alters the lipid profile and metabolism of cultured hepatocytes and human lipoproteins
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ABSTRACT:
PROVIDER: PRJNA953009 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24098181.fastq.gz | Fastqsanger.gz | |||
| SRR24098182.fastq.gz | Fastqsanger.gz | |||
| SRR24098183.fastq.gz | Fastqsanger.gz | |||
| SRR24098184.fastq.gz | Fastqsanger.gz | |||
| SRR24098185.fastq.gz | Fastqsanger.gz |
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Project description:Even though the functions of ANGPTL3 in the circulation are relatively well characterized, many mechanistic questions regarding the molecular consequences of ANGPTL3 loss-of-function and protection against cardiovascular disease remain unanswered. To help understant the molecular mechanisms exerted by ANGPTL3 deficiency, we studied the alterations of ANGPTL3 loss-of-function in hepatocytes and plasma lipid molecular species profiles.
2023-04-06 | GSE229133 | GEO
Project description:Lipoprotein lipase (LPL) carries out the lipolytic processing of triglyceride-rich lipoproteins (TRL) along the luminal surface of capillaries. LPL activity is regulated by angiopoietin-like proteins (ANGPTL3, ANGPTL4, and ANGPTL8), which control the delivery of TRL-derived lipid nutrients to tissues in a temporal and spatial fashion. This regulation mediates the partitioning of lipid delivery to storage and metabolic tissues according to nutritional status. A complex between ANGPTL3 and ANGPTL8 (ANGPTL3/8) inhibits LPL activity in oxidative tissues, but its mode-of-action has remained unknown. Here, we used biophysical techniques to define how ANGPTL3/8 and ANGPTL3 interact with LPL and how they drive LPL inactivation. We demonstrate, by mass photometry, that ANGPTL3/8 is a heterotrimer with a 2:1 stoichiometry between ANGPTL3 and ANGPTL8 and that ANGPTL3 is a homotrimer. Hydrogen–deuterium exchange mass spectrometry (HDX-MS) studies revealed that both ANGPTL3/8 and ANGPTL3 use the proximal portion of their N-terminal α-helices to interact with sequences surrounding the catalytic pocket in LPL. That binding event triggers unfolding of LPL’s α/β- hydrolase domain and irreversible loss of LPL catalytic activity. The binding of LPL to its endothelial transporter protein (GPIHBP1) or to heparan-sulfate proteoglycans protects LPL from inactivation by unfolding, particularly against the unfolding triggered by ANGPTL3. Pulse-labelling HDX-MS studies revealed that ANGPTL3/8 and ANGPTL3 catalyze LPL unfolding in an ATP-independent fashion, which categorize these LPL inhibitors as atypical unfoldases. The catalytic nature of LPL unfolding by ANGPTL3/8 explains why low plasma concentrations of ANGPTL3/8 are effective in inhibiting a molar excess of LPL in capillaries.
2025-03-26 | PXD060125 | Pride
Project description:Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase activities. Recent studies have shed light on the cellular functions of ANGPTL3. However, the precise mechanism underlying its regulation of cellular lipid metabolism remains elusive. We recently reported that ANGPTL3 interacts with the chromatin regulator SMARCAL1, which plays a pivotal role in maintaining cellular lipid homeostasis. Here, through a combination of in vitro and in vivo functional analyses, we provide evidence that ANGPTL3 indeed influences cellular lipid metabolism. Increased expression of Angptl3 prompted the formation of lipid droplets (LDs) in response to slow growth conditions. Notably, under the conditions, Angptl3 accumulated within cytoplasmic peroxisomes, where it interacts with SmarcAL1, which translocated from nucleus as observed previously. This translocation induced changes in gene expression favoring triglyceride (TG) accumulation. Indeed, ANGPTL3 gene knockout (KO) in human cells increased the expression of key lipid genes, which could be linked to elevated nuclear localization of SMARCAL1, whereas the expression of these genes decreased in SMARCAL1 KO cells. Consistent with these findings, the injection of Angptl3 protein to mice led to hepatic fat accumulation derived from circulating blood, a phenotype likely indicative of its long-term effect on blood TG, linked to SmarcAL1 activities. Thus, our results suggest that the Angptl3-SmarcAL1 pathway may confer the capacity for TG storage in cells in response to varying growth states, which may have broad implications for this pathway in regulating energy storage and trafficking.
2025-02-19 | GSE221371 | GEO
Project description:Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase activities. Recent studies have shed light on the cellular functions of ANGPTL3. However, the precise mechanism underlying its regulation of cellular lipid metabolism remains elusive. We recently reported that ANGPTL3 interacts with the chromatin regulator SMARCAL1, which plays a pivotal role in maintaining cellular lipid homeostasis. Here, through a combination of in vitro and in vivo functional analyses, we provide evidence that ANGPTL3 indeed influences cellular lipid metabolism. Increased expression of Angptl3 prompted the formation of lipid droplets (LDs) in response to slow growth conditions. Notably, under the conditions, Angptl3 accumulated within cytoplasmic peroxisomes, where it interacts with SmarcAL1, which translocated from nucleus as observed previously. This translocation induced changes in gene expression favoring triglyceride (TG) accumulation. Indeed, ANGPTL3 gene knockout (KO) in human cells increased the expression of key lipid genes, which could be linked to elevated nuclear localization of SMARCAL1, whereas the expression of these genes decreased in SMARCAL1 KO cells. Consistent with these findings, the injection of Angptl3 protein to mice led to hepatic fat accumulation derived from circulating blood, a phenotype likely indicative of its long-term effect on blood TG, linked to SmarcAL1 activities. Thus, our results suggest that the Angptl3-SmarcAL1 pathway may confer the capacity for TG storage in cells in response to varying growth states, which may have broad implications for this pathway in regulating energy storage and trafficking.
2025-02-19 | GSE221049 | GEO
Project description:Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase activities. Recent studies have shed light on the cellular functions of ANGPTL3. However, the precise mechanism underlying its regulation of cellular lipid metabolism remains elusive. We recently reported that ANGPTL3 interacts with the chromatin regulator SMARCAL1, which plays a pivotal role in maintaining cellular lipid homeostasis. Here, through a combination of in vitro and in vivo functional analyses, we provide evidence that ANGPTL3 indeed influences cellular lipid metabolism. Increased expression of Angptl3 prompted the formation of lipid droplets (LDs) in response to slow growth conditions. Notably, under the conditions, Angptl3 accumulated within cytoplasmic peroxisomes, where it interacts with SmarcAL1, which translocated from nucleus as observed previously. This translocation induced changes in gene expression favoring triglyceride (TG) accumulation. Indeed, ANGPTL3 gene knockout (KO) in human cells increased the expression of key lipid genes, which could be linked to elevated nuclear localization of SMARCAL1, whereas the expression of these genes decreased in SMARCAL1 KO cells. Consistent with these findings, the injection of Angptl3 protein to mice led to hepatic fat accumulation derived from circulating blood, a phenotype likely indicative of its long-term effect on blood TG, linked to SmarcAL1 activities. Thus, our results suggest that the Angptl3-SmarcAL1 pathway may confer the capacity for TG storage in cells in response to varying growth states, which may have broad implications for this pathway in regulating energy storage and trafficking.
2025-02-19 | GSE221048 | GEO
Project description:Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase activities. Recent studies have shed light on the cellular functions of ANGPTL3. However, the precise mechanism underlying its regulation of cellular lipid metabolism remains elusive. We recently reported that ANGPTL3 interacts with the chromatin regulator SMARCAL1, which plays a pivotal role in maintaining cellular lipid homeostasis. Here, through a combination of in vitro and in vivo functional analyses, we provide evidence that ANGPTL3 indeed influences cellular lipid metabolism. Increased expression of Angptl3 prompted the formation of lipid droplets (LDs) in response to slow growth conditions. Notably, under the conditions, Angptl3 accumulated within cytoplasmic peroxisomes, where it interacts with SmarcAL1, which translocated from nucleus as observed previously. This translocation induced changes in gene expression favoring triglyceride (TG) accumulation. Indeed, ANGPTL3 gene knockout (KO) in human cells increased the expression of key lipid genes, which could be linked to elevated nuclear localization of SMARCAL1, whereas the expression of these genes decreased in SMARCAL1 KO cells. Consistent with these findings, the injection of Angptl3 protein to mice led to hepatic fat accumulation derived from circulating blood, a phenotype likely indicative of its long-term effect on blood TG, linked to SmarcAL1 activities. Thus, our results suggest that the Angptl3-SmarcAL1 pathway may confer the capacity for TG storage in cells in response to varying growth states, which may have broad implications for this pathway in regulating energy storage and trafficking.
2025-02-19 | GSE221047 | GEO
Project description:Cardiovascular disease is a leading cause of death worldwide, and inhibition of the hepatically secreted protein ANGPTL3 has emerged as an effective treatment for lowering low-density lipoprotein cholesterol (LDL), the cardinal risk factor for coronary artery disease (CAD). In this study, we examine the effects of complete genetic deficiency of ANGPTL3 on the hepatocyte transcriptome using a HepG2 cell culture model with the ANGPTL3 locus "knocked out" (KO) via CRISPR-Cas9.
2023-05-15 | GSE232045 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE30447: Foxa1 Reduces Lipid Accumulation in Human Hepatocytes and Is Down-regulated in Nonalcoholic Fatty Liver (HepG2 data) GSE30450: Foxa1 Reduces Lipid Accumulation in Human Hepatocytes and Is Down-regulated in Nonalcoholic Fatty Liver (hepatocytes data) Refer to individual Series
2011-07-07 | E-GEOD-30451 | biostudies-arrayexpress
Project description:SMARCAL1 is a chromatin regulator. Biallelic mutations of SMARCAL1 cause Schimke Immunoosseous Dysplasia (SIOD), a disease with severe growth defects and premature death. Atherosclerosis and hyperlipidemia are common phenotypes among SIOD patients. However, little is known about their genesis and development. Here we show that SMARCAL1 is vital in regulating cellular lipid metabolism. Using a proteomic approach, we found that SmarcAL1 interacts with angiopoietin-like 3 (Angptl3), a key lipoprotein regulator. SmarcAL1 deficiency in cell models resulted in substantial accumulation of triglycerides (TGs) and fatty acids (FAs). SmarcAL1 KO in mice drastically increased plasma TG level. The nuclear SmarcAL1 translocates into cytoplasm, surprisingly, enriched at peroxisomes, where it interacts with Angptl3. This shuttling provides a regulatory control over cellular lipid metabolism via SmarcAL1-regulated gene expression, in response to cell growth states. Inactivation of SmarcAL1 gene reduced the expression of the genes responsible for FA metabolism, suggesting that SmarcAL1 plays a key role in regulating lipid metabolism. Indeed, the Angptl3-mediated TG partition is largely dependent on SmarcAL1 activity. This activity was further supported by two opposite SMARCAL1 single-tissue expression profiles linked to two quantitative trait loci that are differentially associated with body mass index. Thus, SMARCAL1 is crucial for cellular lipid metabolism, and ANGPTL3-regulated SMARCAL1 activities enable cells to response to cell growth states for TG storage or expenditure.
2024-01-02 | GSE221373 | GEO
Project description:Purpose: The goal of this study was to evaluate the effect of ANGPTL3 inhibition on liver transcriptomes in LDLR KO mice. Methods: Mice were treated once weekly for 3 weeks with 25mg/kg control mAb or ANGPTL3 mAb. Livers were harvested 6 days after the last mAb treatment. Results: ANGPTL3 inhibition had no major impact on hepatic gene expression.
2020-07-05 | GSE143726 | GEO